AU2002227921B2 - Pyrimidine derivatives - Google Patents

Description

2,4,5,-TRISUBSTITUTED PYRIMIDINE DERIVATIVES FIELD OF INVENTION The compound of the invention has activity in biological systems and more particularly has activity as an antagonist to neurokinin 1 receptors.

BACKGROUND

The neuropeptide receptor for substance P (NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes.

The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson's disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).

Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn's disease, ocular injury and ocular inflammatory diseases reviewed in "Tachykinin Receptor and Tachykinin Receptor Antagonists", J. Auton. Pharmacol., 13, 23-93, 1993.

Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).

The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.

In addition, in The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin- 1-receptor antagonist.

[R:\L1BA106752.doc:JJP -2- Furthermore, U.S. Pat. No. 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.

The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in "Neuropeptides, 32(1), 1-49, (1998)" and "Eur. J. Pharmacol., 383(3), 297-303, (1999)".

Life Sci., (2000), 67(9), 985-1001 describes, that astrocytes express functional receptors to numerous neurotransmitters including substance P, which is an important stimulus for reactive astrocytes in CNS development, infection and injury. In brain to tumors malignant glial cells originating from astrocytes are triggered by tachykinins via NK-1 receptors to release soluble mediators and to increase their proliferative rate.

Therefore, selective NK-1 receptor antagonists may be useful as a therapeutic approach to treat malignant gliomas in the treatment of cancer.

A paper in Nature (London) (2000), 405(6783), 180-183 describes that mice with a genetic disruption of NK-1 receptor show a loss of the rewarding properties of morphine.

Consequently NK-1 receptor antagonists may be useful in the treatment of withdrawal symptoms of addictive drugs such as opiates and nicotine and reduction of their abuse/craving.

NK1 receptor antagonists have been reported to have also a beneficial effect in the therapy of traumatic brain injury (Paper presented by Prof. Nimmo at the International Tachykinin Conference 2000 in La Grande Motte, France, Oct. 17-20, 2000 with the title "Neurokinin 1 (NK-1) Receptor Antagonists Improve the Neurological Outcome Following Traumatic Brain Injury" (Authors: A. J. Nimnmo, C. J. Bennett, X. Hu, I.

Cernak, R. Vink).

The compounds of the present invention are further useful for the treatment of benign prostatic hyperplasia (BPH), which is common in older men. BPH can be progressive and lead to urinary retention, infections, bladder calculi and renal failure. This indication has been reported in EP 01109853.0.

SUMMARY

The present invention is a compound of the formula [R:\LIBA]06752.doc:JJP -3- R' N I wherein R' is lower alkyl, lower alkoxy, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, S(0) 2 -lower alkyl, -N(Ra)-(CH 2 )n-N(Rb) 2

(CH

2 )n-N(R) 2 -N(Rd) 2 or a cyclic tertiary amine of the group RS or a cyclic tertiary amine of the group

RS

that contains one additional heteroatom, selected from N, O or S, said cyclic tertiary amine being connected to a pyrimidine ring of formula 1 or connected to said pyrimidine ring via the linker -O(CH 2

R

2 is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;

R

3

/R

3 are, independently from each other, hydrogen or lower alkyl;

(R

4 )m are, independently from each other in the case where m is not 0 or 1, halogen, trifluoromethyl or lower alkoxy;

R

5 is hydrogen or lower alkyl; R, Ra, R b R, Rd, Re, R f are, independently from each other, hydrogen or lower alkyl; X is or Y is -SO 2 or n is 1,2,3 or 4; and mis 0, 1 or 2; and a pharmaceutically acceptable acid addition salt thereof.

[R:\LBA]06752.doc:JJP -4- The compounds of formula I and their salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G proteincoupled receptors.

The compounds of the present invention are further useful for the treatment of benign prostatic hyperplasia (BPH), which is common in older men. BPH can be o0 progressive and lead to urinary retention, infections, bladder calculi and renal failure. This indication has been reported in EP 01109853.0.

The compounds of formula I can also be used in the form of their prodrugs, for example in form of their N-oxides. The prodrugs may add to the value of the present compounds advantages in adsorption, pharmacokinetics in distribution and transport to the brain.

Objects of the present invention are the compounds of formula I and pharmaceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.

DETAILED DESCRIPTION As used herein, the term "lower alkyl" denotes a saturated straight- or branchedchain alkyl group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms.

The term "halogen" denotes chlorine, iodine, fluorine and bromine.

The term "lower alkoxy" denotes a group wherein the alkyl residue is as defined above, and which is attached via an oxygen atom.

As used in this disclosure, the term "cyclic tertiary amine" denotes a five or six membered heterocylic ring moiety, having at least one N atom which is always connected to the pyrimidine ring of formula I, or a five or six membered heterocylic ring moiety with one nitrogen atom which is always connected to the pyrimidine ring of formula I having one additional N, O or S atom, including but not limited to, for example, [R:\LIBA]06752.doc:JJP 4a pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholin-l,1-dioxo or thiomorpholin-1-oxo and the like.

The term "pharmaceutically acceptable acid addition salt" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.

The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders or emesis by the administration of NK-1 o0 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities.

Preferred are compounds of formula I, in which X is -C(O)N(CH 3 )-and Y is Exemplary preferred compounds of this group are those, wherein R' is a cyclic tertiary amine, for example the following compounds: [R:\LIBA]06752.doc:JJP WO 02/42280 PCT/EPOI/13084 2- (4-methyl-piperazin- 1-yl)-4-o-tolyloxy-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl) -methyl-amide, 2-piperazin- 1-yl-4-o-tolyloxy-pyrimidine-5-carboxylic acid benzyl)-methyl-amide or 4-(2-chloro-phenoxy)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboyic acid trifluoromethyl-benzyl) -methyl-amide.

Further preferred compounds of the above mentioned group are those, wherein R' is

-O-(CH

2 )-cyclic tertiary amine or the group -O-(CH 2

)-NR

2 Such compounds are 2-(2-morpholin-4-yl-ethoxy)-4-o-tolyloxy-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl) -methyl-.amide or 2-(2-dimethylamino-ethoxy)-4-o-tolyloxy-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl) -methyl-amide.

Further preferred are compounds of formula 1, in which X is -N(CH 3 and Y is Exemparly preferred compounds of this group are those, wherein R' is -S-lower alkyl, for example the following compounds: 2-(3 ,5-bis-trifluoromethyl-phenyl) -N-methyl-N- (2-methylsulfanyl-4-o-tolyloxy- 2-(3,5-bis-trifluoromethyl-phenyl) [4-(4-fluoro-phenoxy)-2-methylsulfanyl-pyrimidin- -N-methyl-isobutyramide or 2-(3,5-bis-trifluoromethyl-phenyl)-N- (2-cbloro-phenoxy)-2-methylsulfanyl- -N-methyl-isobutyramide.

Further preferred compounds of the above group are those, wherein R' is a cyclic tertiary amine, for example the following compounds: 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-4-o-tolyloxy- 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N- [2-(4-methyl-piperazin- l-yl)-4-o- -isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-piperazin- 1-yl-4-o-tolyloxy- -isobutyramide, 3o 2-(3,5-bis-trifluoromethyl-phenyl)-N- [4-(4-fluoro-phenoxy)-2-(4-methyl-piperazin-1 yl) -pyrimidin-5-yll -N-methyl-isobutyramicle, 2- 3,5-bis-trifluoromethyl-phenyl)-N- [4-(4-fluoro-phenoxy) -2-piperazin- 1 -yl-pyrimidin- -N-methyl-isobutyramide, 2- (3,5-bis-trifluoromethyl-phenyl)-N- [4-(2-cbloro-phenoxy)-2-morpholin-4-ylpyrimidin-5-yll -N-methyl-isobutyramide, 2- (3,5-bis-trifiuoroinethyl-phenyl)-N- [4-(2-cloro-phenoxy)-2-(4-methyl-piperazin- 1- -N-methyl-isobutyramide or -6- 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenoxy)-2-piperazil- 1 -yl-pyrimidin- -N-methyl-isobutyramide.

Preferred compounds of this group are fuirther those, wherein R1 is N(Ra)(CH 2 ),,Nkb 2 for example the following compounds: 2-(3,5-bis-trifluoromethyl-phenyl)-N-[2-(2-dimethylamino-ethylamino)-4-o-tolyloxyor 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-12-(2-dimethylamino-ethylamino)-4-(4-fluoro- Further preferred compounds of this group are those, wherein R 1 is -O(CH 2 ),,-CYCliC tertiary amine or the group -O(CH 2

),,NRC

2 for example the following compounds: 2-(3 ,5 -bis-trifluoromethyl-phenyl)-N-methy1-N-II2-(2-morpholin-4-yl-ethoxy)-4-o- 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenoxy)-2-(2-morpholin-4-yl- 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-[2-(2-dimethylamino-ethoxy)-4-o-tolyloxy- -N-methyl-isobutyramide, 2-(3 ,5 -bis-trifluoromethyl-phenyl)-N-[2-(3 -dimethylamino-propoxy)-4-o-tolyloxy- -N-methyl-isobutyramide, 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-[2-(2-dimethylamino-ethoxy)-4-(4-fluoro-phenoxy)- 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-[2-(3 -dimethylamnino-propoxy)-4-(4-fluoro- 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-[2-(2-dimethylamino-ethoxy)-4-(2-chloroor 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-[2-(3 -dimethylamino-propoxy)-4-(2-chloro- [R:\LIBA]06752.doc:JJP 6a- Also preferred is a compound of formula I wherein X is wherein Re is lower alkyl, Y is and R 2 is lower alkyl. Yet another preferred compound of formula I is a compound wherein X is wherein is hydrogen, R 2 is lower alkyl and Y is A further preferred compound of formula 1 is wherein X is -C(O)NRe-, wherein Re is lower alkyl, Y is and R 2 is hydrogen. An additional preferred compound of formula I is wherein X is wherein Re is lower alkyl, Y is -0and R 2 is halogen. Yet another additional preferred compound of formula I is wherein X is wherein Re is lower alkyl, Y is and Re is lower alkoxy. Another preferred compound of formula I is wherein X is -N(Rf)C(O)-wherein R f is lower alkyl, Y is and R 2 is lower alkyl. Yet another preferred compound of formula I is wherein X is wherein R f is lower alkyl, Y is and R 2 is halogen.

The present compound of formula I and pharmaceutically acceptable salts thereof can be prepared by methods known in the art, for example, by processes described below, which process comprises reacting a compound of formula [R:\LIBA]06752.doc:JJP -7with a compound of formula halK

R

3 to a compound of formula wherein Y, R 2

R

3

R

3

R

4 R (for the purposes of these reaction schemes, the designation includes R, Ra, R b R d, R d

R

e R) and m have the significances given above, or reacting a compound of formula with a compound of formula [R:\LIBA]06752.doc:JJP

(R

4 )m NHR R 3 R 3

V

to give a compound of formula Y 0 R 3 R 3 N (R 4) RI lb

R

1

'N

wherein Y, R1, R R" R 4 R (for the purposes of these reaction schemes, the designation includes R, Ra, Rb, Rd, R, Rf) and mn have the significances given above, or reacting a compound of formula Y 0 I NHR

V

R N with a compound of formula

(R

4 )m hal R 3 R 3

VII

to a compound of formula y 0 R 3 R 3 I I )m l R N [R:\LIBA106752.doc:JJP wherein hal is Cl, Br or I, and Y, R 1

R

2

R

3

R

3

R

4 R (for the purposes of these reaction schemes, the designation includes R, Ra, R b

R

C

R

d

R

e

R

f and m have the significances given above, or reacting a compound of formula with a compound of formula

(R

4 )m

NHR

R

3

R

3 to a compound of formula wherein Y, R 2

R

3

R

3

R

4 R (for the purposes of these reaction schemes, the designation includes R, Ra, Rb, R c Rd, Re and m have the significances given above, or alkylating a compound of formula

R

2 Y 0 R 3 R3' N NH N(R4)m

R&.N

to a compound of formula [R:\LIBA106752.doc:JJP T U R"R' or T r K K.

N S(R4)m I N T- -(R4)m

R

1 N R o Ib la wherein Y, R 1

R

2

R

3

R

3

R

4 R (for the purposes of these reaction schemes, the designation includes R, Ra, Rb, R R d

R

e

R

f and m have the significances given above, or transforming a compound of formula

R

2 X(R4)m YS R

I-

S 3 R 3 to a compound of formula

.(R

4

R

3

R

3 wherein X, Y, R 2 R R, R 4 and m have the significances given above, or reacting a compound of formula

,(R

4 m

R

3

R

3 with a corresponding cyclic or non cyclic amine to a compound of formula [R:\LIBA]06752.doc:JJP 11

R

2 S(R4) N X R3 R3 A N 1-3 or with a corresponding alcohol to a compound of formula

R

2 R Y

(R

4

R

3

R

3 B N 1-4 wherein Y, X, R 1

R

2

R

3

R

3

R

4 and m have the significances given above, A is

(CH

2 )n-N(R) 2

-N(R)

2 or a cyclic tertiary amine of the formula and B is lower alkoxy, -O-(CH 2 )n-N(R) 2 or /(CH2)n-Oand R 5 is described as above, or modifying one or more substituents R 1

R

2

R

3

R

3

R

4 or R (for the purposes of these reaction schemes, the designation includes R, R a

R

b

R

e

R

d Re, R within the definitions given above, and if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.

In accordance with process variant a) DIPEA (N-ethyldiisopropyl-amine) is added to a mixture of a compound of formula II and of a compound of formula III in dichloromethane and the mixture is stirred at temperatures between 25-40 0 C. The desired compound of formula Ia is isolated after purification in good yields.

Process variant b) describes the reaction of a compound of formula IV with a compound of formula V to a compound of formula Ib. The reaction is carried out in [R:\LIBA]06752.doc:JJP WO 02/42280 PCT/EP01/13084 -12conventional manner, for example in a solvent like toluene in the presence oftriethylamine. The mixture is refluxed for about 1 hour.

In accordance with process variant c) a compound of formula Ib is prepared. This reaction is carried out with DIPEA (N-ethyldiisopropyl-amine) which is added to a mixture of a compound of formula VI and of a compound of formula VII in dichloromethane.

A further method for the preparation of a compound of formula Ib is described in process variant A compound of formula VIII is treated with a compound of formula V in the presence of EDCI (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide and HOBT (1-hydroxybenzotriazole hydrate) and triethylamine in conventional manner.

Compounds of formulas Ia or Ib may be prepared by alkylating the -NH-linking group with a corresponding lower alkyl iodine in the presence of NaH in DMF in accordance with process variant e) in conventional manner.

In accordance with process variant f) a compound of formula I-1 is treated with m- CPBA in dichloromethane to give a compound of formula 1-2. Furthermore, this compound may then be treated with a corresponding cyclic amine, such as morpholine, piperazine or methyl-piperazine to a corresponding compound of formula I-3 or with a corresponding alcohol, such as 2-dimethylaminoethanol or N-(2hydroxyethyl)morpholine, to a corresponding compound of formula 1-4 in accordance with process variant g).

The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration.

Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methan-sulphonates, p-toluenesulphonates and the like are examples of such salts.

The following schemes 1-4 describe the processes for preparation of compounds of formula I in more detail. The starting materials are known compounds or may be prepared according to methods known in the art.

In the schemes the following abbreviations have been used: DIPEA N-ethyldiisopropyl-amine EDCI 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HOBT 1-hydroxybenzotriazole hydrate DMF dimethylformamid m-CPBA m-chloroperbenzoic acid 13

DPPA

diphenyiphosphoryl azide Scheme I OH 0 N R N Ix RiAN X11 Pool 3 hal

N~

R IlN OH XI acetnitrile Cs 2 00 3 R2 N)-R OH R NVIlII.

ethanol NaOH EDCI,HOBT,NEt 3 CH 2 C1 2

R

2 R3, R 3 and R 4 have the significances given above and R (for the purposes of these reaction schemes, the designation includes R, RW RIl, Rc, Rd, Rf) is lower alkyl.

14- Scheme 2 qR 2 Y 0 N

OH

NaH,DMF

RI

(R 4

M

EDCI,HOBT, NEt 3

CH

2

CI

2

N

R

A

R',R

2

R

3 R 3 R 4 and Y have the significances given above and R (for the purposes of these reaction schemes, the designation includes R, Rb, Rc, Rd, Re, Rf) is lower alkyl.

Scheme 3 (R 4 )m9 (R 4 )m Y m-.CPBA

Y

R CH 2

CI

2 R, 3

R

3

N

Ii 0 12 amine dioxane (R 4 )m 13 aicohol,Cs 2 00 3 acetoitril 15

R

3

R

4 X, Y anid mn have the significances given above, A is

N(R)-(CH

2 2

-N(R)

2 or a cyclic tertiary amine of the formula and B is lower alkoxy, -O-(CH 2 )n-N(R) 2 Or

A,,CH

2 )11-O- R0 and is described as above.

Scheme 4

Y

N

OH

R N Vill NaH, RI

DMF

R

OHDPPA, NEt 3 Y THF N~ KYro, R N .0N Y R HO!, MeOH yo NHW NN 0 NH Nxv

R

1

N-

R 2 I (R 4M

N

R1 1 N' 1 a XiV 0

(R)M

ha R 3 R 3

I

CH,C 2

DIPEA

R (for the purposes of these reaction schemes, the designation includes R, Ra, Rb, R,

R

d

R

e

R

1

R

2

R

3

R

3

R

4 Y and m have the significance given above.

As mentioned earlier, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.

The compounds were investigated in accordance with the tests given hereinafter.

[R:\LEBA]06752.doc:JJP -16- The affinity of test compounds for the NKI receptor was evaluated at human NKI receptors in CHO cells infected with the human NKI receptor (using the Semliki virus expression system) and radiolabelled with substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04 leupeptin (8 pg ml), MnCl 2 (3mM) and phosphoramidon (2 pM). Binding assays consisted of 250 pl of membrane suspension (1.25x10 5 cells assay tube), 0.125 1l of displacing agent and 125 1l of 3 H]substance P. Displacement curves were determined with at least seven concentrations of the compound. The assay tubes were incubated for min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI with 2 x 2 ml washes of HEPES buffer (50 mM, pH The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments.

The affinity to the NK-1 receptor, given as pKi, is in the scope of 6.00 9.38 for the described compounds.

Examples of the pKi data for such compounds are described in the table below: Example No. pKi 1 7.38 4 8.54 7 8.33 11 6.77 7.55 19 6.71 23 7.01 29 6.50 39 7.79 44 7.70 49 9.04 WO 02/42280 PCT/EP01/13084 -17- 52 9.10 63 8.02 73 7.49 The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, drag6es, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, drag6es and hard gelatine capsules.

Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc.

Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.

Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.

Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.

Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily 4 -18dosage of about 10 to 1000 mg per person of a compound of f ormula I should be appropriate, although the above upper limit can also be exceeded when necessary.

The following Exam pies illustrate the present invention without limiting it. All temperatures are given in degrees Celsius.

Example 1 2 -Methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carbox-ylic acid (3 benzyl)-methyl-aniide a) 2 -Methylsulfanyl-4-o-tolyloxy'-pyrimidine-5- arboxlic acid ethyl ester To a solution of 5.40 a (23.31 mnmol) 4 -chloro-2-rnethylsulfany1-pyrimidine-5-carboxylic acid ethyl ester in 150 ml acetonitrile 3.26 a (30.17 mmol) o-cresol and 30.25 g (92.83 mmol) CS2CO 3 were added and the reaction mixture was stirred for 14 h at RT. The suspension was poured into ice-water and extracted two times with CH 2

C

2 The combined organic phases were dried (Nal-SO 4 filtered and evaporated to give 7.0 (99 2acid ethyl ester, which was directly used for the next step b) 2 -Methansulfonvl-4-o-tolyloUr-pyimidine-5-carbo2 rlic acid To a solution of 7.0 a (23.0 mmol) 2 acid ethyl ester in 50 ml ethanol a solution of 1.37 g (34.50 mmol) sodiumnhydroxide in ml water was added and the resulting mixture was stirred 1 h at RT. The pH of the solution was adjusted to 1 with 25% HCl. The mixture was extracted twice with GH 2

CI

2 The combined organic phases were dried (NaSO 4 filtered and evaporated. The resulting solid was triturated twice with 10 mld diisopropylether, filtered off and dried to give 3.00 g (47 2 -methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid as a colorless solid, MS (ISN): 257.1 c) 2 -MethylsulfanyL-4-o-tolvloxv-p2yrimidine5carbo2;lic acid benzvl) -methyl-amide To a solution of 1.0 g(3.62 mmol) 2 acid in 60 ml CH 2 Cl 2 1.0 ml (7.24 mmol) triethylamine, 0.554 a (3.62 mmol) 1-hydroxybenzotriazole and 0.69 g (3.62 mmol) N-(3-dimethylaminopropyl)-N'-ethylcarbodiiAde hydrochloride 1.11 g (4.34 mmol) (3,5-bis-trifiuormethyl-benzyl)-methyl-amin were added. The reaction mixture was stirred for 16 hrs. The reaction mixture was diluted with ml CH 2 C12, washed with 50 ml 0.5N HCl and 50 ml H 2 0. The aqueous layers were backextracted with 50 ml CH 2 Cl 2 The combined organic layers were dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2

GH

2 Cl 2 /MeOH,40:1) to give 1.80 a (96 2 -methylsulfanyl-47o-tolyloxy-pyrimidine-5- WO 02/42280 PCT/EPOI/13084 19 carboxylic acid (3,5-bis-trifluorornethyl-benzyl)-methyl-amide as a colorless foam, MS 515 Example 2 2-Methanesulfonyl-4-o-tolyloxy -pyrimidine-5-carboxylic acid benzyl)-methyl-amide To a solution of 1.70 g (3.30 mmol) 2-methylsulfan-yl-4-o-tolyloxy-pyrimidine-5carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 70 ml CH 2 C1 2 2.03 g (8.24 mmol) 3-chioroperbenzoic acid (70 was added at 5 0 and the reaction mixture stirred for 2 hrs. at RT. After addition of 150 ml sat. NaHCO 3 -solution, the layers were separated, the organic phase washed with sat. NaHC03-solution, dried (Na 2

SO

4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2

CI

2 /eth-yl acetate 9:1) to give 1.50 g (83 2-methanesulfonyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid as a colorless solid, MS (ISP): 548.1 (M+H)t.

Example 3 2-Morpholin-4-yl-4-o-tolyloxy-pyrimidine-5-carboxylic acid benzyl)-methyl-amide To a solution of 0.2 g (0.37 mmol) 2-methanesulfonyl-4-o-tolyloxy-pyrimidine-5carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 10 ml dioxane 0.08 ml (0.91 mmol) morpholine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH 2 Cl 2 and 50 ml

H

2 0. The aqueous layer was extracted with 50 ml CH 2 Cl 2 the combined organic layers dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (Si0 2

CH

2 Cl 2 -/MeOH 40:1) to give 0.18 g(88 2-morpholin-4-yl-4-o-totyloxyacid (3,5-bis-trifluoromethyl-benzyl)--methy-amide as a colorless oil, MS (ISP): 555.2 Example 4 2- (4-Methyl-piperazin- 1-yl)-4-o-tolyloxy-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide To a solution of 0.25 g (0.46 mmol) 2-methanesulfonyl-4-o-tolyloxy-pyrimidine-5carboxylic acid (3,5-bis-trifiuoromethyl-benzyl)-methyl-amide in 10 ml dioxane 0.12 ml 14 mmol) I -nethylpiperazine was added. The reaction mixture was stirred for 16 hrs.

After evaporation of the solvent, the residue was distributed between 50 ml CI- 2 C1 2 and ml H 2 0. The aqueous layer was extracted with 50 ml CH 2 Cl 2 the combined organic WO 02/42280 PCT/EPOI/13084 20 layers dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2

CI

2 /MeOH/NH 4 QH 140: 10:1) to give 0.2 g (77 2-(4methyl-piperazin- l-yl)-4-o-tolyloxy-pyrimidine-5-carboxylic acid trifiuoromethyl-benzyl)-methyl-amide as a colorless foam, MS (ISP): 563.3 Example 2-Piperazin-1-yl-4-o-tolyloxy-pyrimidine-5-carboxyllc acid benzyl)-methyl-ainide To a solution of 0.32 g (0.58 mmol) 2-methanesulfonyl-4-o-tolyloxy-pyrimidine-5carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 10 ml dioxane 0.125 g (1.46 mmol) piperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml GH 2 Cl 2 and 50 mld

H

2 0. The aqueous layer was extracted -with 50 ml CH 2 Cl 2 the combined organic layers dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (Si0 2

CH

2 Cl 2 IMeOH/NH 4 OH 110: 10: 1) to give 0.25 g (77 2-piperazin-1I-yl-4-oacid (3,5-bis-trifiuoromethyl-benzyl)-methyl-amide as a colorless foam, MS (ISP): 554.2 Example 6 2-(2-Dimethylamino-ethylaminio)-4-o-tolyloxy-pyrimidine-5-carboxylic acid trifiuoromethyl-benzyl)-methyl-amide To a solution of 0.25 g (0.46 mmol) 2-methanesulfonyl-4-o-tolyloxy-pyrimidine-5carboxylic acid (3,5-bis-trifluoromnethyl-benzyl)-methyl-amide in 10 ml dioxane 0.125 ml 14 mmol) 2-dimethylaminoethylamine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml

CH-

2

CI

2 and 50 ml H 2 0. The aqueous layer was extracted with 50 ml CH 2 Cl 2 the combined organic layers dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2

CL

2 /MeOH-/NH 4 OH 140:10:1) to give 0.15 g (59 2-(2dimethylamino-ethylamino) -4-o-tolyloxy-p-yrimidine-5-carboxylic acid trifiuoromethyl-benzyl)-methyl-amide as a colorless foam, MS (ISP): 556.2 Example 7 2-(2-Morpholin-4-yl-ethoxy)-4-o-tolyloxy-p-yrimidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide To a solution of 0.2 g (0.37 mmol) 2-methanesulfonyl-4-o-tolyloxy-pyrimidine-5carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 10 ml acetonitrile 0.066 WO 02/42280 PCT/EPOI/13084 -21ml (0.55 mmol) N.-(2-hydroxyethyl)morpholine and 0.595 gu (1.83 mmol) Cs 2

CO,

3 were added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH 2

CL

2 and 50 ml H 2 0. The aqueous layer was extracted with 50 ml.CH 2 Cl 2 the combined organic layers dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2 Cl 2 /MeOH/NH 4

OH

140:10:1) to give 0.12 g (54 2-(2-morpholin-4-yl-ethoxy)-4-o-tolyloxy-pyrimidine-5carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless foam, MS (ISP): 599.1 Example 8 2-(2-Dimethylamiino-ethoxy)-4-o-tolyloxy-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide To a solution of 0.25 g (0.46 mmol) 2-mnethanesulfonyl-4-o-tolyloxy-pyrimidine-5carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 10 ml acetonitrile 0.069 ml (0.68 mmol) 2-dimethylaminoethanol and 0.743 g (2.28 MMOl) Cs 2 00 3 were added.

The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH 2 Cl 2 and 50 ml H 2 0. The aqueous layer was extracted with 50 ml CH 2 Cl 2 the combined organic layers dried (MgSO 4 filtered and evaporated.

The residue was purified by chromatography (Si0 2

CH

2 Cl 2 /MeOH/NH 4 OH 140: 10: 1) to give 0.15 g (59 2-(2-dimethylamino-ethoxy)-4-o-tolyloxy-pyrimidine-5-carboxylic acid as a light yellow oil, MS (ISP): 557.3

(M±H)

t Example 9 2-Methylstulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid methyl-amnide In an analogous manner to that described in Example 1c) there was obtained from 2acid and methyl-amine 2-methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid 3o dimethoxy-benzyl)-methyl-amide as a colorless oil, MS 439.1 (M t 1).

Example 2-Methanesulfonyl-4-o-tolyloxy-yrimidine-5-carboxylic acid methyl-amnide In an analogous manner to that described in Example 2 there was obtained from 2acid (3,5-dimethoxy-benzyl) WO 02/42280 PCT/EPOI/13084 22 methyl-amide and 3-cloroperbenzoic acid 2-methanesulfonyl-4-o-tolyloxy-py-rimidine-5carboxylic acid (3,5-dimethoxy-benzyl)-methyl-amide as a colorless foam, MS (ISP): 472.1

(M+H)

t Example 11 2-(4-Methyl-piperazin- 1-yl)-4-o-tolyloxy-pyrimidine-5-carboxylic acid benzyl)-methyl-amide In analogous manner to that described in Example 4 there was obtained from 2-methanesulfonyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid methyl-amide and 1 -methylpiperazine 2-(4-mnethyl-piperazin-l -yl)-4-o-tolyloxyacid (3,5-dimethoxy-benzyl) -methyl-amide as a colorless foam, MS (ISP): 492.3 Example 12 2-(2-Dimethylamino-ethoxy)-4-o-tolyloxy-p-yrimidine-5-carboxylic acid benzyl)-methyl-amide In analogous manner to that described in Example 8 there was obtained from 2-methanesulfonyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid methyl-amide and 2-dimethylaminoethanol 2- (2-dimethylamino-ethoxy)-4-o-tolyloxypyrimidine-5-carboxylic acid (3,5-dimethoxy-benzyl)-methyl-amide as a colorless oil, MS (ISP): 481.4 Example 13 2-Methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid methyl-amide In an analogous manner to that described in Example 1c there was obtained from 2acid and (3,5-dimethyl-benzyl) methyl-amine 2-methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid benzyl)-methyl-arnide as a colorless oil, MS (ISP): 408.3 Example 14 2-Methanesulfonyl-4-o-toloxy-pyrimidine-5-carboxylic acid methyl-amide In an analogous manner to that described in Example 2 there was obtained from 2methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid (3,5-dimethyl-benzyl) -methylamide and 3-cbloroperbenzoic acid 2-methanesulfonyl-4-o-tolyloxy-pyrimidine-5- WO 02/42280 PCT/EPOI/13084 23 carboxylic acid (3,5-dimethyl-benzyl)-methyl-amide as a colorless foam, MS (ISP): 440.4 Example 2- (4-Methyl-piperazin-1-yl)-4-o-tolyloxy-pyrimidine-5-carboxylic acid benzyl)-methyl-amide In an analogous manner to that described in Example 4 there was obtained from 2acid methyl-amide and 1-methylpiperazine 2- (4-methyl-piperazin- 1-yl)-4-o-tolyloxyacid (3,5-dimethyl-benzyl)-methyl-amide as a white foam, MS (ISP): 460.5 Example 16 2-(2-Dimethylamino-ethoxy)-4-o-tolyloxy-pyrimidine-5-carboxylic acid benzyl)-methyl-amide In an analogous manner to that described in Example 8 there was obtained from 2acid methyl-amide and 2-dimethylaminoethanol 2-(2-dimethylamino-ethoxy)-4-o-tolyloxyacid (3,5-dimethyl-beinzyl)-methyl-amide as a colorless oil, MS (ISP): 449.5 Example 17 2-Methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid In an analogous manner to that described in Example 1c) there was obtained from 2acid and 3,5-dicblorobenzylamine 2methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxyic acid 3,5-dichloro-benzylamide as a light yellow oil, MS 433 Example 18 2-Methanesulfonyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid In an analogous manner to that described in Example 2 there was obtained from 2acid 3,5-dichloro-benzylamide and 3-chloroperbenzoic acid 2-methanesulfonyl-4-o-tolyloxy-pyiimidine-5-carboxylic acid as a colorless solid, MS (ISP): 466.2 WO 02/42280 PCT/EPOI/13084 24 Example 19 2-(4-Methyl-piperazin- l-yl)-4-o-tolyloxy-pyrimidine-5-carboxylic acid benzylamide In an analogous manner to that described in Example 4 there was obtained from 2methanesulfonyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid 3,5-dichloro-benzylamide and 1-methylpiperazine 2-(4-methyl-piperazin- l-yl) acid 3,5-dichloro-benzylamide as a colorless solid, MS (ISP): 486.3 Example 2-Methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid methyl-amide To a solution of 0.6 og (1.8 mmol) 2-methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid 3,5-dicbloro-benzylamide in 20 ml N,N-dimethylformamide 0.096 g (2.4 mmol) sodiumnhydride (60 dispersion in mineraloil) was added and the mixture stirred for 1 h.

After the addition of 0.18 ml (2.9 mmol) methyl iodide at the reaction mixture was stirred for 3 hrs. at RT. The reaction mixture was distributed between 50 ml H 2 0, 50 Ml brine and 50 ml CH 2

CI

2 The phases were separated, and the aqueous layer extracted twice with 50 Ml CH 2 Gl 2 The combined organic layers were dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2 Cl 2 /ethyl acetate 19:1) to give 0.5 g (610/) 2-methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid dichloro-benzyl)-methyl-amide as a light yellow oil, MS 447.1 Example 21 2-Methanesulfonyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid methyl-amide In an analogous manner to that described in Example 2 there was obtained from 2acid amide and 3-chloroperbenzoic acid 2-methanesulfonyl-4-o-tolyloxy-pyrimidine-5carboxylic acid (3,5-dichloro-benzyl)-methyl-amide as a colorless foam, MS (ISP): 480.2 Example 22 2-(4-Methyl-piperazin- 1-yl)-4-o-tolyloxy-pyrimnidine-5-carboxylic acid benzyl)-methyl-amide In an analogous manner to that described in Example 4 there was obtained from 2acid WO 02/42280 PCT/EPOI/13084 25 amide and 1-methylpiperazine 2-(4-methyl-piperazin- carboxylic acid (3,5-dichloro-benzyl)-methyl-amide as a colorless foam, MS (ISP): 500.2 (M Example 23 2-Methylsulfanyl-4-phenoxy-pyrimidine-5-carboxylic acid benzyl)-methyl-amide In an analogous manner to that described in Example Ila) there was obtained from 4acid ethyl ester and phenol 2methylsulfanyl-4-phenoxy-pyrimidine-5-carboxylic acid ethyl ester, which was saponified as described in Example 1b) and reacted with amine to give as described in Example 1c) 2-methylsulfanyl-4-phenoxy-pyrimidine-5carboxylic acid (3,5-bis-trifiuoromethyl-benzyl)-methyl-amide as a colorless solid, MS (TSP): 501 Example 24 2-Methanesulfonyl-4-phenoxy-pyrimidine-5-carboxylic acid benzyl)-methyl-aniide In an analogous manner to that described in Example 2 there was obtained from 2methylsulfanyl-4-phenoxy-pyrimidine-5-carboxylic acid (3,5-bis-trifiuoromethyl-benzyl) methyl-amide and 3-chloroperbenzoic acid 2-methanesulfonyl-4-phenoxy carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless solid, MS (TSP): 533 Example 2-(4-Methyl-piperazin- 1-yl)-4-phenoxy-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide In an analogous manner to that described in Example 4 there was obtained from 2acid benzyl)-methyl-amide and 1 -methylpiperazine 2-(4-methyl-piperazin- l-yl)-4-phenoxyacid (3,5-bis-trifluoromethyl-benzyl) -methyl-amide as a colorless solid, MS (ISP): 554.2 Example 26 4- (2-Chloro-phenoxy)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide WO 02/42280 PCT/EPOI/13084 26 In an analogous manner to that described in Example 1a) there was obtained frm 4acid ethyl ester and 2-chloro phenol 4- (2-chioro-phenoxy) -2-methylsulfanyl-pyrimnidine-5-carboxylic acid ethyl ester which was saponified as described in Example 1b) and reacted with methyl-amine to give as described in Example 1c) 4-(2-chloro-phenoxy)-2-(4-methylpiperazin-l -yl) -pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide as a colorless solid, MS (ISP): 536.2 (M±H) t Example 27 4- (2-Ghloro-phenoxy)-2-methanaesulfonyl-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide In an analogous manner to that described in Example 2 there was obtained from 4-(2chloro-phenoxy)-2- (4-methyl-piperazin- 1-yl) -pyrimnidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide and 3-chloroperbenzoic acid 4-(2-cblorophenoxy) -2-methanesulfony]-pyrimidine-5-carboxylic acid benzyl)-methyl-amide as a colorless solid, MS (ISP): 560.0 t Example 28 4- (2-Gbloro-phenoxy)-2-(4-methyl-piperazin- 1-yl)-pyrimidine-5-carboxylic acid trifiuoromethyl-benzyl)-methyl-amide In an analogous manner to that described in Example 4 there was obtained from 4- (2acid trifiuoromethyl-benzyl)-methyl-amide and I1 -methylpiperazine 4-(2-chloro-phenoxy)-2- (4-methyl-piperazin-l -yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifiuoromethyl-benzyl) methyl-amide as a colorless solid, MS (ISP): 588.2 Example 29 4-(2-Methoxy-phenoxy)-2- (4-methyl-piperazin- 1-yl)-p-yrimidine-5-carboxylic acid bis-trifiuoromethyl-benzyl)-rnethyl-amide In an analogous manner to that described in Example 1a) there was obtained from 4acid ethyl ester and 2-methoxyphenol 4- (2-methoxy-phenoxy)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester which was saponified as described in Example 1b) and reacted with benzyl)-methyl-amine to give as described in Example 1c) 4-(2-methoxy-phenoxy)-2-(4methyl-piperazin- 1-yl)-pyrimidine-5-carboxylic acid methyl-amide as a colorless solid, MS (ISP): 532.1 (M±H) t WO 02/42280 PCT/EPOI/13084 -27- Example 4-(2-Methoxy-phenoxy)-2-methanesulfonyl-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide In an analogous manner to that described in Example 2 there was obtained from 4-(2mnethoxy-phenoxy)-2- (4-ruethyl-piperazin- 1-yl)-pyrimidine-5-carboxylic acid trifiuoromethyl-benzyl) -methyl-amnide and 3-chloroperbenzoic acid 4-(2-methoxyacid benzyl)-methyl-amide as a colorless solid, MS (ISP): 564.2 (M+H) t Example 31 4-(2-Methoxy--phenoxy)-2- (4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid bis.-trifluoromethyl-benzyl)-methyl-amide In an analogous manner to that described in Example 4 there was obtained from 4-(2methoxy-phenoxy)-2-methanesulfonyl-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide and 1 -methylpiperazine 4-(2-methoxy-phenoxy) 2-(4-methyl-piperazin-1 -7l)-pyrimidine-5-carboxylic acid benzyl)-methyl-amide as a colorless solid, MS (ISP): 584.1 Example 32 2-(2-Dimethylam-ino-ethylamino)-4-(2-methoxyphenoxy)-pyrimidine-5-carboxylic acid In an analogous manner to that described in Example 6 there was obtained from 4-(2acid trifluoromethyl-benzyl) -methyl-amide and 2-dimethylaminoethylamine 2- (2dimethylamino-ethylamino) -4-(2-methoxy-phenoxy)-pyrimidine-5-carboxylic acid bis-trifiuoromethyl-benzyl)-methyl-amide as a colorless solid, MS (ISP): 572.1 (M-iH) t Example 33 4-(2-Fluor-phenoxy)-2-methansulfonyl-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amidde In an analogous manner to that described in Example la) there was obtained from 4acid ethyl ester and 4-fluoro- phenol 4- (4-fiuoro-phenoxcy)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester which was saponified as described in Example ib) and reacted with methyl-amine to give as described in Example 1c) 4-(4-fiuoro-phenoxy)-2- WO 02/42280 PCT/EPOI/13084 28 acid amide as a colorless solid, MS (ISP): 520.1 (M+H t Example 34 4-(4-Fluoro-phenoxy)-2-methanesulfonyl-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide In an analogous manner to that described in Example 2 there was obtained from 4-(4acid beuzyl) -methyl-amide and 3-chloroperbenzoic acid 4-(4-fluoro-phenoxy)-2methanesulfonyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoronaethyl-benzyl) -methylamide as a colorless solid, MS (ISP): 552.0 Example 4-(4-Fluoro-phenoxy)-2- (4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide In an analogous manner to that described in Example 4 there was obtained from 4-(4fluoro-phenoxy) -2-methanesulfonyl-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide and 1-methylpiperazine 4- (4-fluoro-phenoxy) -2- (4-methyl-piperazin- 1-yl)-pyrimidine-5-carboxylic acid methyl-amide as a white foam, MS 571 Example 36 4-(4-Fluoro-phenoxy)-2-piperazin- 1-yl-pyrirnidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide In an analogous manner to that described in Example 5 there was obtained from 4-(4acid trifluoromethyl-benzyl)-methyl-amide and piperazine 4- (4-fluoro-phenoxy) -2-piperazinacid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless foam, MS (ISP): 558.2 Example 37 2- (2-Dimethylamino-ethylamino)-4- (4-fluoro-phenoxy)-pyrimidine-5-carboxylic acid In an analogous manner to that described in Example 6 there was obtained from 4-(4fluoro-phenoxy)-2-methanesulfonyl-pyrimidine-5-carboxylic acid trifluorometh-yl-benzyl)-methyl-amide and dimethylaminoethylamine 2-(2- WO 02/42280 PCT/EPOI/13084 -29dimethylamino-ethylamino) -4-(4-fluoro-phenoxy) -pyrimidine-5-carboxylic acid trifiuoromethyl-benzyl)-methyl-amide as a colorless foam, MS (ISP): 560.2 Example 38 2-(2-Dimethylamino-ethoxy)-4- (4-fluoro-phenoxy)-pyrimidine-5-carboxylic acid bis-trifluoromethyl-benzyl)-methyl-amide In an analogous manner to that described in Example 8 there was obtained from 4-(4fluoro-phenoxy) -2-methanesulfonyl-pyrimidine-5-carboxylic acid trifiuoromethyl-benzyl)-methyl-amide and 2-dimethylaminoethanol 2-(2-dimethylaminoethoxy) -4-(4-fiuoro-phenoxy) -pyrimidine-5-carboxylic acid benzyl)-methyl-amide as a colorless foam, MS (ISP): 561.3 (Mi-H)

T

Example 39 2-Pyridin-4-yl-4-o-tolyloxy-pyrimidine-5-carboxylic acid benzyl)-methyl-amide a) 4-Chloro-2-pyridin-4-yLI-pyr:imidine-5-carboxy lic acid ethyl ester A suspension of 4.73 g (19.5 mmol) 4-hydroxy-2--pyridin-4-yl-pyrimidine-5-carboxylic acid ethyl ester in 20 Ml POCI 3 was heated at refiux for 1 h. The solution was cooled to RT and poured into 100 ml ice-water. The pH- of the solution was adjusted to 8 with sat.NaHCO 3 -solution. The water-phase was extracted three times with 80 ml CH 2

C

2 The combined organic phases were dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (Si0 2

CH

2 Cl 2 /MeOI- 40: 1) to give 4.34 g (84 4-chloro-2acid ethyl ester as a yellow solid, MS 263.1 b) 2-Pyridin-4-yl-4-o-tolyloxv-pyrimidine-5-carbox yic acid ethyl ester A suspension of 0.6 g (2 28 mmol) 4-chloro-2-pyridin-4-yl-pyrimicline-5-carboxylic acid ethyl ester, 0.27 g (2 50 mmol) o-cresol and 2.97 g(9.10 mmol) Cs 2

CO

3 in 15 ml acetonitrile was stirred for 17 h at RT. The suspension was poured into 150 ml H 2 0 and extracted three times with 90 ml ethyl acetate. The combined organic phases were dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2 ethyl acetate/MeOH- 100:1) to give 0.74 (97 2-pyridin-4-yl-4-o-tolyloxy-pyrimidineacid ethyl ester as a yellow solid, MS 335.1 c) 2-Pyidin-4-L-4-o-tolylox;y-pyrimidine-5-carboxylic acid To a solution of 0.70 g (2.08 mmol) 2 -pyridin-4-yl-4-o-tolyloxy-pyrimidine-5-carboxylic acid ethyl ester in 20 ml ethanol a solution of0. 12 g (3.12 mmol) sodiumhydroxide in ml water was added and the resulting mixture was stirred 2 h at RT. The pH1 of the solution WO 02/42280 PCT/EPOI/13084 30 was adjusted to 3 with 25% HCL The mixture was extracted twice with CH 2 Cl 2 The combined organic phases were dried (Na 2

SO

4 filtered and evaporated. The resulting solid was triturated twice with 10 ml ethanol, filtered off and dried to give 0.60 g (94 2pyridin-4-yl-4-o-tolyloxy-pyrimidine-5-carboxylic acid as a colorless solid, MS 307.1 d) 2-Pyridin-4-yl-4-o-tolyloxv-pyrimidine-5-carboxcylic acid benzyl) -methyl-amide To a solution of 0.35 g(1.14 mmol) 2-pyridin-4-yl-4-o-tolyloxy-pyrimidine-5-carboxylic acid in 20 ml CH 2

CI

2 0.32 ml (2.28 mmol) triethylamine, 0.15 g (1.14 mmol) 1-hydroxybenzotriazole and 0.22 g 14 mmol) N- (3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride 0.33 g (1.37 mniol) (3,5-bis-trifluorrnethyl-benzyl)-methyl-amin were added. The reaction mixture was stirred for 16 hrs. The reaction mixture was diluted with ml CH 2

CI

2 and washed 50 ml H 2 0. The organic layer was dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2 Cl2/MeOH 19: 1) to give 0.33 g (53 2-pyridin-4-yl-4-o-tolyloxy-pyrimidine-5-carboxylic acid bistrifluoromethyl-benzyl)-methyl-amide as a colorless foam, MS (ISP): 547.1 Example 4-(4-Fluoro-phenoxy)-2-pyridin-4-y-pyrimicline-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide In an analogous manner to that described in Example 39 b) there was obtained fromn 4chloro-2-pyridin-4-yl-pyrimidine-5-carboxylic acid ethyl ester and 4-fluorphenol 4- (4fluoro-phenoxy)-2-pyridin-4-yl-pyrimidine-5-carboxylic acid ethyl ester, which was saponified as described in Example 39 c) and reacted with (3,5-bis -trifluormethyl-benzyl)methyl-amine to give as described in Example 39 d) 4-(4-fiuoro-phenoxy)-2-pyridin-4-ylacid (3,5-bis-trifluoromethyl-benzyl)~-methyl-amide as a colorless foam, MS (ISP): 55 1.0 Example 41 2-Methyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid methyl-amide In an analogous manner to that described in Example 39 b) there was obtained from 4acid ethyl ester and o-cresol 2-methyl-4-oacid ethyl ester, which was saponified as described in Example 39 c) and reacted with (3,5-bis -trifluormethyl-benzyl)-meth-yl-amine to give as WO 02/42280 PCT/EPOI/13084 31 described in Example 39 d) 2-methyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid trifluoromethyl-benzyl) -methyl--amidle as a colorless foam, MS 483 Example 42 2-Phenyl-4-o-tolyloxypyrimidine-5-carboxylic acid methyl-amide In an analogous manner to that described in Example 39 b) there was obtained from 4acid ethyl ester and o-cresol 2-phenyl-4-oacid ethyl ester, which was saponified as described in Example 39 c) and reacted with (3,5-bis-trifiuormethyl-benzyl)-methyl-amine to give as described in Example 39 d) 2-phenyl-4-o-tolyloxy-pyrimidile-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide as a colorless foam, MS (ISP): 546.1 (M+H) t Example 43 4-o-Tolyloxy- [2,2ilbipyrimidinyl-5-carboxylic acid methyl-amide a) 4-1-ydrox y- 2,2'1 bipyimidinyl-5-carboxylic acid ethyl ester To a fresh prepared solution of sodiumethanolate in ethanol (prepared from 0.44 g (18.92 mmol) Na in 20 nml Ethanol) 1.50 g (9.46 mmol) pyrimidine-2--carboxamidine hydrochloride was added. After 10 min. 1.89 ml (9.46 mmol) diethyl.

ethoxymethylenemalonate was added at 0 0 and the resulting suspension was stirred for 12 hrs. After addition of 20 mnl H 2 0, the pH was adjusted to 5 and the aqueous phase was extracted three times with CH 2

CI

2 The combined organic phases were dried (Na 2

SOJ,

filtered and evaporated. The residue was triturated with 5 ml diisopropylether, filtered off and dried to give 1.62 g (70 4-hydroxy- [2,2'1bipyrimidinyl-5-carboxylic acid ethyl ester as a light yellow powder, MS 246.1 (MW).

4-Chloro- r2,2' lbipyrimidinyl-5-carboxylic acid ethyl ester A suspension of 1.62 g (6.5 mmol) 4-hydroxy- [2,2']bipyrimidinyl-5-carboxyiic acid ethyl ester in 16 Ml POC1 3 was heated at refiux for 1h. The solution was cooled to RT and poured into 100 ml ice-water. The pH of the solution was adjusted to 8 with sat. NaHCO 3 solution.The water phase was extracted three times with 80 ml GH 2

CI

2 The combined organic phases were dried (Na 2

SO

4 filtered and evaporated. The residue was purified by chromatography (Si0 2

CH

2 C1 2 !MeOH 95:5) to give 1.43 g (82 4-chioro- WO 02/42280 PCT/EPOI/13084 32 [2,2']bipyrimidinyl-5-carboxylic acid ethyl ester as a light brown solid, MS 264.1 c) 4-o-Tolyloxy- f2,2' ]bipyrjimidinyl-5-carboxylic acid ethyl ester To a solution of 1.43 g (5.4 mmol) 4-chloro-[2,2']bipyrimidinyl-5-carboxylic acid ethyl ester in 35 ml acetonitrile 0.5 g (7.0 mmol) o-cresol and 7.0 g (21.6 mmol) Cs 2

CO

3 were added and the reaction mixture stirred for 14 hrs at RT. The suspension was poured into ice-water and extracted two times with CH 2 Cl 2 The combined organic phases were dried (Na 2

SO

4 filtered and evaporated. The residue was purified by chromatography (SiC 2

GH

2

CI

2 /MeOH 19:1) to give 0.96 g (53 4-o-tolyloxy-[2,2'lbipyrimidinyl-5-carboxylic acid ethyl ester as a light yellow solid, MS (ISP): 337.2 (M+H) t d) 4-o-Tolyloy- bipyrimidinyl-5-carboxylic acid To a solution of 0.33 g (0.98 mmol) 4-o-tolyloxy-[2,2'lbipyrimidinyl-5-carboxylic acid ethyl ester in 15 ml ethanol 3.68 ml 0.4 N NaCH was added and the resulting solution was stirred for 2 hrs at RT. The pH of the solution was adjusted to 4 with IN HCl. The aqueous solution was extracted three times with CH 2 Cl 2 The combined organic phases were dried (Na 2

SO

4 filtered and evaporated. The resulting solid was triturated twice with diethyl ether, filtered off and dried to give 0.26 g (85 4-o-tolyloxy- [2,2']bipyrimidinyl-5carboxylic acid as a light yellow solid, MS (ISN): 307.3 4-o-Tolvloxy- 2,2']bipyrimidinyl-5-carboxvlic acid methyl-amide To a solution of 0.25 g (0.83 mmol) 4-o-tolyloxy-[2,2']bipyrimidinyl-5-carboxylic acid in ml CLI 2

C

2 0.23 ml (1.6 mmol) triethylamine, 0. 13 g 83 mmol) 1 -hydroxybenzotriazole and 0.16 g (0.83 mmol) N- (3-dlimethylaminopropyl)-N'-ethylcarbodiimidc hydrochloride 0.25 g (1 mmol) (3,5-bis-trifluormethyl-benzyl)methyl-amin were added.The reaction mixture was stirred for 16 hrs. The reaction mixture was diluted with ml CH- 2 C1 2 washed with 50 ml 0.5N HCl and 50 ml CH 2 C1 2 The combined organic layers were dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2 Cl 2 /MeOH 19:1) to give 0.39 g (86 4-o-tolyloxy- [2,21 bipyrimidinyl-5-carboxylic acid (3,5-bis-trifiuoromethyl-benzyl)-meth-yl-amide as a light yellow foam, MS (ISP): 548.1 (M+H) t WO 02/42280 PCT/EPOI/13084 -33- Example 44 2-Thiomorpholin-4-yl-4-o-tolyloxy -pyrimidine-5-carboxylic acid trifluoromethyl-benzyl)-methyl-amide To a solution of 0.79 g (1.44 mmol) 2-methansulfonyl-4-o-tolyloxy-pyrimidine-5carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 40 ml dioxane 0.34 ml (3.6 mmol) thiomorpholine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH 2 Cl 2 and 50 ml

H

2 0. The aqueous layer was extracted with 50 ril CH 2

CI

2 the combined organic layers dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2 Cl 2 /MeOH 40:1) to give 0.48 g (59 2-thiomorpholin-4-yl-4-o-tolyloxyacid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless solid, MS (ISP): 571.1 Example 2-(1 ,1-Dioxo- 12i-thiomorpholin-4-yl)-4-o-tolyloxy-pyrimidine-5-carboxylic acid bis-trifluoromethyl-benzyl)-methyl-amide To a solution of 0.44 g (0.77 mmol) 2-thiomorpholin-4-yl-4-o-tolyloxy-pyrimidine-5carboxylic acid (3,5-bis-trifiuoromethyl-benzyl)-methyl-amide in 25 ml GH 2 Gl 2 0.48 g (1.93 mmol) 3-chloroperbenzoicacid (70 was added at 5 'an the reaction mixture was stirred for 1 h at RT. After addition of 50 ml sat. NaHCO,;-solution, the layers were separated, the organic phase washed with NaH-CO 3 -solution, dried (Na 2

SO

4 filtered and evaporated. The residue was purified by chromatography (Si0 2

CH

2 Cl 2 /ethyl acetate 4: 1) to give 0.42 g (91 1,1-dioxo- 1X 6 -thiomorpholin-4-yl)-4-o-tolyloxy-pyrimidine-5carboxylic acid (3,5-bis-trifiuoromethyl-benzyl)-methyl-amide as a colorless solid, MS (ISP): 602.9 (M+H) t Example 46 2-(3,5-Bis-trifluoromethyl-phenyl)-N-niethyl-N- (2-methylsulfanyl-4-o-tolyloxya) (2-Methylsulfanyl-4-o-tolyloxv-pyrimidin-5-yl) -carbamic acid tert.-bqtyl ester To a solution of 1.90 g 6.88 mmol) 2-methylsulfanyl-4-o-tolyloxy-pyrimidine-5carboxylic acid, 0.95 ml triethylamine (6.88 mmol) and 1.29 ml (1.37 mmol) t-butanol in ml THE, 1.47 ml (6.88 mmol) diphenylphosphorylazide were added and the resulting solution heated at refiux for 12 hrs. After evaporation of the solvent, the residue was distributed between GH 2 01 2 and H 2 0. The aquoeus phase was extracted twice with 80 mlA

CH

2 Cl 2 The combined organic layers were dried (Na 2

SO

4 filtered and evaporated. The residue was purified by chromatography (Si0 2

CH

2 Cl 2 ethyl acetate 40:1) to give 1.70 g WO 02/42280 PCT/EPOI/13084 34 (71 (2-methylsulfanyl-4-o-tolyloxcy-pyrimidin-5-yl)-carbamic acid tert.-butyl ester as a colorless solid, MS (ISP): 348.2 t b) Methyl-(2-methylsulfanyl-4-o-tolylo2xy-pyrimidin-5-yl)-carbamic acid tert-butyl ester To a solution of 1.60 g (4.61 mmol) (2-methylsulfanyl-4-o-tolyloxy-pyrimidin-5-yl)carbamic acid tert.-butyl ester in 20 ml N,N-dimethylformamide 0.25 g (6.4 mmol) sodiumnhydride (60% dispersion in mineraloil) was added and the reaction mixture stirred for 1 h. After the addition of 0.48 ml 7.83 mmol) methyl iodide at the reaction mixture was stirred for 3 hrs. The reaction mixture was poured into 100 ml ice-water and three times extracted with 80 ml CH 2 C1 2 The combined organic layers were dried (Na 2

SO

4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2 Cl 2 /ethyl acetate 19:1) to give 1.60 g(98 methyl-(2-methylsulfanyl-4-o-tolyloxyacid tert-butyl ester as a colorless oil, MS 361 c) Methyl-(2-meth To a solution of 1.60 g (4.43 mmol) methyl-(2-methylsulfanyl-4-o-tolyloxy-pyrimidin-5yl)-carbamic: acid tert.-butyl ester in 20 ml CH 2 Gl 2 2 ml trifluoracetic acid was added and the reaction mixture stirred for 2 hrs. at 400. The reaction mixture was poured into icewater and the pH of the solution adjusted to 10 with 1N NaOH solution. The aqueous phase was extracted three times with 80 ml CH 2

C

2 The combined organic layers were dried (Na2SO 4 filtered and evaporated to give 1. 10 g (95 methyl-(2-methylsulfanyl-4o-tolyloxy-pyrimidin-5-yl)-amine as a white solid, MS 261 d) 2.-(3,5-Bis-trifiuoromethyl-phenl) -N-metyl-N-(2-methylsulfan 1-4-o-tolyloxy -isobgtyamide To a solution of 1.10 g (4.21 mol) methyl-(2-methylsulfanyl-4-o-tolyloxy-pyrimidin-5-yl)amine and 1.44 ml (8.42 mmol) N-ethyldiisopropylamine in 30 Ml CH 2

CI

2 a solution of 1.87 g (5.89 mmol) 2-(3,5-bis-trifiuormethyl-phenyl)-2-methyl-propiony chloride in 5 ml

CH

2

CI

2 was added and the reaction mixture stirred for 12 hrs at RT. The reaction mixture was poured into 50 ml 0.5 N NaOH-solution.The phases were separated and the aqueous phase three times extracted with 80 ml CH 2 Cl 2 The combined organic layers were dried (Na 2

SO

4 filtered and evaporated. The residue was purified by chromatography (SiO 2 hexane/ ethyl acetate 2:1) to give 2.10 g (92 2-(3,5-bis-trifluoromethyl-phenyl)-Nmethyl-N-(2-methylsulfanyl-4-o-tolyloxy-pyrimidin-5-yl) -isobutyramide as a white foam, MS (ISP): 544.2 Example 47 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(2-methanesulfonyl-4-o-tolyloxy-py-rimidin-5-yl)- N-methyl-isobutyramnide WO 02/42280 PCT/EPOI/13084 35 To a solution of 2.00 g (3.68 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2in 80 ml CH 2 Cl 2 2.26 g (9.20 mmol) 3-chloroperbenzoic acid (70 was added at 5 0 and the reaction mixture stirred for 2 hrs. at RT. After addition of 150 ml sat. NaHCO 3 -solution, the layers were separated, the organic phase washed with sat. NaHCO 3 -solution, dried (Na 2

SO

4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2 C1 2 /ethyl acetate 19: 1) to give 1.90 g (83 2-(3,5-bis-trifiuoromethyl-phenyl)-N-(2-methanesulfonyl-4-oas a white foam, MS 575 Example 48 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N- (2-morpholin-4-yl-4-o-tolyloxy- To a solution of 0.2 g (0.35 mmol) 2-(3,5-bis-trifiuoromethyl-phenyl)-N-(2in 10 ml dioxane 0.076 ml (0.87 mmol) morpholine was added. The reaction mixture was stirred for 16 hrs.

After evaporation of the solvent, the residue was distributed between 50 ml CH 2 C1 2 and ml sat. NaHCO 3 -solution. The aqueous layer was extracted with 50 ml CI- 2 C1 2 the combined organic layers dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2 Cl 2 /methanol 50: 1) to give 0. 17 g (84 2-(3,5-bistrifluoromethyl-phenyl)-N-methyl-N- (2-morpholin-4-yl-4-o-tolyloxy-pyrimidin-5-yl)isobutyramide as a white foam, MS (TSP): 583.2 (Mi-H) t Example 49 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N- (4-methyl-piperazin- 1-yl)- 4 -o- To a solution of 0.22 g (0.38 mmol) 2-(3,5-bis-trifiuoromethyl-phenyl)-N-(2in 10 ml dioxane 0. 106 ml (0.96 mmol) 1 -methylpiperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml

GH

2 Cl 2 and 50 ml sat. NaHGO 3 -solution. The aqueous layer was extracted with 50 mld

CH

2 Cl 2 the combined organic layers dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2

GH

2

CI

2 /MeOH/NH 4 OH 110:10:1 to give 0.11 g (48 2- (3,5-bis-trifluorornethyl-phenyl)-N-rnethyl-N- [2-(4-methyl-piperazin- l-yl) -4-o- -isobutyramide as a white foam, MS (TSP): 596.2 WO 02/42280 PCT/EPOI/13084 -36- Example 2-(3,5-Bis-trifiuoromethyl-phenyl)-N-methyl-N-(2-piperazin- l-yl-4-o-tolyloxy- To a solution of 0.30 g (0.52 mmol) 2-(3,5-bis-trifiuoromethyl-phenyl)-N-(2methanesulfonyl-4-o-tolyloxy-pyrimidin-5-yl)-N-methyl-isobutyramide in 10 ml dioxane 0. 112 (1.3 mmol) piperazine was added. The reaction mixture was stirred for 16 hrs.

After evaporation of the solvent, the residue was distributed between 50 ml CH 2 C1 2 and ml sat. NaHCO 3 -solution. The aqueous layer was extracted with 50 Ml CH- 2

CI

2 the combined organic layers dried (M-SO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2

CI

2 /MeOH-/NH 4 OH 140:10:1 to give 0.20 g (66 2-(3,5bis-trifluoromethyl-phenyl)-N-methyl-N- (2-piperazin- 1-yl-4-o-tolyloxy-pyrimidin-5-yl)isobutyramide as a white foam, MS (ISP): 582.2 Example 51 2-(3,5-Bis-trifluoromethyl-phenyl)-N- [2-(2-dimethylamino-ethylamino)-4-o-tolyloxy- -N-methyl-isobutyramide To a solution of 0.25 g (0.43 mmol) 2-(3,5-bis-trifiuoromethyl-phenyl)-N-(2in 10 ml dioxan 0. 119 ml (1.09 mmol) 2-dimethylaminoethylamine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between ml CH 2 Cl 2 and 50 nil sat. NaHCO 3 -solution. The aqueous layer was extracted with 50 ml

CH-

2 C1 2 the combined organic layers dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2

GH

2 Cl 2 /methanol/NH 4 OH 140: 10:1 to give 0.20 g (79 2-(3,5-bis-trifiuoromethyl-phenyl) [2-(2-dimethylamino-ethylamino)-4-otolyloxy-pyrimidin-5-yl] -N-methyl-isobutyramide as a white foam, MS (ISP): 584.2 Example 52 2-(3,5--Bis-trifluoromethyl-phenyl)-N-methyl-N- [2-(2-morpholin-4-yl-ethioxy)-4-otolyloxy To a solution of 0.4 g (0.7 mmol) 2-(3,5-bis-trifiuoromethyl-pheniyl)-N-(2in 20 ml acetonitrile 0.126 ml (1.04 mmol) N-(2-hydroxyethyl)morpholine and 1.13 g (3.48 mmol) Cs 2

CO

3 were added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH 2 Cl 2 and 50 ml H 2 0. The aqueous layer was extracted with 50 ml CH 2 Cl 2 the combined organic layers dried (MgSO 4 WO 02/42280 PCT/EPOI/13084 37 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2 ClJ/MeDH 40:1) to give 0.30 g (69 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl- N- [2-(2-morpholin-4-y-ethoxy)-4-o-tolylocy-pyrimidin-5-yl] -isobutyramide as a colorless foam, MS (ISP): 627.2 (M±H) t Example 53 2- (3,5-Bis-trifluoromethyl-phenyl)-N- (2-dimetbylamino-ethoxy)-4-o-tolyloxy- -N-methyl-isobutyramide To a solution of 0.25 g (0.43 mmol) 2-(3,5-bis-trifiuoromethyl-phenyl)-N-(2io methanesulfonyl-4-o-tolyloxy-pyrimidin-5--yl)-N-methyl-isobutyramide in 10 ml acetonitrile 0.066 ml (0.65 mnmol) 2-dimethylaminoethanol and 0.70 g (2.14 mmol)

CS

2

CO

3 were added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH 2 Cl 2 and 50 ml H 2 0. The aqueous layer was extracted with 50 ml CH 2 Cl 2 the combined organic layers dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (Si0 2

CH

2 Cl 2 /MeOH/NH 4 OH 110:10:1) to give 0.18 g (71 2-(3,5-bis-trifiuoromethylphenyl)-N- (2-dimethylamino-ethoxy)-4-o-tolyloxy-pyrimidin-5-yl] -N-methylisobutyramide as a colorless foam, MS (ISP): 585.2 (M Example 54 2-(3,5-Bis-trifluoromethyl-phenyl)-N- [2-(3-dimetbylamino-propoxy)-4-o-tolyloxy- -N-methyl-isobutyramide To a solution of 0.30 g (0.52 mmol) 2-(3,5-bis-trifiuoromethyl-phenyl)-N-(2in 20 ml acetonitrile 0.061 ml (0.78 rnmol) 2-dimethylamninopropanol and 0.85 g (2.61 mmol) Cs 2

CO

3 were added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH 2 Cl 2 and 50 ml H 2 0. The aqueous layer was extracted with 50 ml CH 2 Cl 2 the combined organic layers dried (MgSO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH-

2

C

2 /MeOH-/NH 4 OH 140:10:1) to give 0.20 g (64 2-(3,5-bis-trifiuoromethylphenyl)-N-[2- (2-dimethylamino-propoxy) -4-o-tolyloxy-pyrimidin-5-yl] -N-methylisobutyramide as a colorless oil, MS (ISP): 599.2 Example 2-(3,5-Bis-trifluoromethyl-phenyl)-N- (4-fiuoro-phenoxy)-2-methylsulfanyl- WO 02/42280 PCT/EPOI/13084 -38- In an analougous manner to that described in Examle 46 a) there was obtained from 4-(4acid, diphenyiphosporylazide and t-butanol (4-fluoro-phenoxy)-2-methylsulfanyl-pyrimidin-5-yl] -carbamic acid tert.-butyl ester, which was methylated with methyliodide and than deprotected with trifluoracetic acid according to Example 43 b) The resulting [4-(4-fluoro-phenoxy)-2- -methyl-amine was treated with 2- phenyl)-2-methyl-propionyl chloride as described in Example 43 e) to give 2-(3,5-bistrifluoromethyl-phenyl)-N- (4-fluoro-phenoxy) -2-methylsulfanyl-pyrimidin-5-yl] -Nmethyl-isobutyramide as a white foam, MS 547 Example 56 2- (3,5-Bis-trifluoromethyl-phenyl)-N- [4-(4-fluoro-phenoxy)-2-methanesulfonyl- -N-methyl-isobutyramide In an analogous manner to that described in Example 47 there was obtained ftrm 2-(3,5bis-trifluoromethyl-phenyl)-N- [4-(4-fluoro-phenoxy)-2-methylsulfanyl-pyrimidin-5-yl] N-methyl-isobutyramide and 3-chloroperbenzoic acid 2-(3,5-bis-trifluoromethyl-phenyl)- N- (4-fluoro-phenoxy) -2-methanesulfonyl-pyrimidin-5-y] -N-methyl-isobutyramide as a white foam, MS (ISP): 580.2 Example 57 2- (3,5-Bis-trifluoromethyl-phenyl)-N- (4-fluoro-phenoxy)-2-morpholin-4-yl- -N-methyl-isobutyrmide In an analogous manner to that described in Example 48 there was obtained from 2-(3,5bis-trifluoromethyl-phenyl)-N- (4-fluoro-phenoxy) yl] -N-methyl-isobutyramide and morpholine 2- (3,5-bis-trifluoromethyl-phenyl)-N-[4- (4-fluoro-phenoxy)-2-morpholin-4-yl-pyrimidin-5-yl] -N-methyl-isobutyramide as a colorless foam, MS (ISP): 587.2 Example 58 2- (3,5-Bis-trifluoromethyl-phenyl)-N- (4-fluoro-phenoxy)-2- (4-methyl-piperazin- 1- -N-methyl-isobutyramide in an analogous manner to that described in Example 49 there was obtained from 2-(3,5bis-trifluoromethyl-phenyl)-N- [4-(4-fluoro-phenoxy)-2-methanesulfonyl-pyrimidin-5yl] -N-methyl-isobutyramide and 1 -methylpiperazine 2- N- [4-(4-fluoro-phenoxy) (4-methyl-piperazin- 1-yl)-pyrimidin-5-yl] -N-methylisobutyramide as a colorless foam, MS (ISP): 600.1 WO 02/42280 PCT/EPOI/13084 -39- Example 59 2-(3,5-Bis-trifluoromethyl-phenyl)-N- (4-fluoro-phenoxy)-2-piperazin- 1-yl-pyrimidin- -N-methyl-isobutyramide In an analogous manner to that described in Example 50 there was obtained from 2-(3,5bis-trifluoromethyl--phenyl)-N- [4-(4-fluoro-phenoxy)-2-methanesulfonyl-pyrimidin-5yl] -N-methyl-isobutyramide and piperazine 2-(3,5-bis-trifluoromethyl-phenyl)-N- fluoro-phenoxy) -2-piperazin- l-yl-pyrimidin-5-yl] -N-methyl-isobutyramide as a colorless foam, MS (ISP): 586.2 Example 2- (3,5-Bis-trifluoromethyl-phenyl)-N- (2-dimethylamino-ethylamino)-4- c4-fluoro- -N-methyl-isobutyramide In an analogous manner to that described in Example 51 there was obtained from 2-(3,5bis-trifluoromethyl-phenyl) (4-fluoro-phenoxy)-2-methanesulfonyl-pyrimidin-5yl] -N-methyl-isobutyramide and 2-dimethylaminoethylamine 2- phenyl)-N- [2-(2-dimethylamino-ethylamino)-4-(4-fluoro-phenoxy)-pyrimidin-5-yl] -Nmethyl-isobutyramide as a colorless foam, MS (ISP): 588.3 Example 61 2- (3,5-Bis-trifluoromethyl-phenyl)-N- (4-fluoro-phenoxy)-2- (2-morpholin-4-yl- -N-methyl-isobutyramide In an analogous manner to that described in Example 52 there was obtained fr om 2-(3,5bis-trifluoromethyl-phenyl)-N- [4-(4-fluoro-phenoxy)-2-methanesulfonyl-pyrimidin-5yl] -N-methyl-isobutyramide and N- (2-hydroxyethyl) morpholine 2- trifluorom ethyl -phenyl) 4- fluoro-phen oxy) -2 (2-m orpholin-4-yI- ethoxy) -N-methyl-isobutyramide as a colorless foam, MS (ISP): 631.1 Example 62 2- (3,5-Bis-trifluoromethyl-phenyl)-N- (2-dimethylamino-ethoxy)-4- (4-fluoro- -N-methyl-isobutyramide In an analogous manner to that described in Example 53 there was obtained from 2-(3,5bis-trifluoromethyl-phenyl)-N- [4-(4-fiuoro-phenoxy)-2-mnethanesulfonyl-pyrimidin-5yl] -N-methyl-isobutyramide and 2-dimethylaminoethanol 2-(3,5-bis-trifluoromethyl- WO 02/42280 PCT/EPOI/13084 phenyl) (2-dimethylamino-ethoxy) (4-fluoro-phenoxy)-pyrimidin-5-yl] -Nmethyl-isobutyramide as a colorless foam, MS (ISP): 589.2 Example 63 2- (3,5-Bis-trifluoromethyl-phenyl)-N- 12- (3-dimethylamino-propoxy)-4-(4-fluoro- -N-methyl-isobutyramide In an analogous manner to that described in Example 54 there was obtained from 2-(3,5bis-trifluoromethyl-phenyl) [4-(4-fluoro-phenoxy) yl] -N-methyl-isobutyramide and 2-dimethylaminopropanol 2-(3,5-bis-trifluoromethylphenyl) (2-dimethylamino-ethoxy) (4-fluoro-phenoxy)-pyrimidin-5-yl] -Nmethyl-isobutyramide as a colorless foam, MS (ISP): 603.1 Example 64 2-(3,5-Bis-trifluoromethyl-phenyl)-N- [4-(2-chloro-phenoxy)-2-methylsulfanylpyrimidin-5-yll -N-methyl-isobutyramide In an analougous manner to that described in Examle 46 a) there was obtained from 4-(2chioro-phenoxy) -2-methylsulfanyl-pyrimidine-5-carboxylic acid, diphenyiphosphorylazide and t-butanol [4-(2-chloro-phenoxy)-2-methylsulfanyl- -carbamic acid tert.-butyl ester, which was methylated with methyliodide and than deprotected whit trifluoracetic acid according to Example 43 b) The resulting (2-chloro-phenoxy)-2-methylsulfanyl-pyrimidin-5-yl] -methyl-amnine was treated with 2- (3,5-bis-trifiuormethyl-phenyl)-2-methyl-propiony chloride as described in Example 43 e) to give 3,5-bis-trifluoromethyl-phenyl) (2-chloro-phenoxy) -2-methylsulfanyl- -N-methyl-isobutyramide as a white foam, MS (ISP): 564.2 (M±H) t Example 2- (3,5-Bis-trifluoromethyl-phenyl)-N- (2-chloro-phenoxy)-2-methanesulfonyl- In an analogous manner to that described in Example 47 there was obtained from 2-(3,5bis-trifluoromethyl-phenyl)-N- [4-(2-cbloro-phenoxy)-2-methylsulfanyl-pyrimidin-5-yl] N-methyl-isobutyramide and 3-cbloroperbenzoic acid 2-(3,5-bis-trifluoromethyl-phenyl) N- [4-(2-chloro-phenoxy)-2-methanesulfonyl-pyrimidin-5-yl -N-methyl-isobutyrarnide as a white foam, MS (ISP): 596.1 (M±H) t WO 02/42280 PCT/EPOI/13084 41 Example 66 2- (3,5-Bis-trifluoromethyl-phenyl)-N- (2-chloro-phenoxy)-2-morpholin-4-yl- -N-methyl-isobutyramide In an analogous manner to that described in Example 48 there was obtained from 2-(3,5bis-trifluoromethyl-phenyl)-N- (2-chloro-phenoxy)-2-methanesulfonyl-pyrimidin-5yl] -N-methyl-isobutyramide and morpholine 2-(3,5-bis-trifluoromethyl-phenyl)-N- [4- (2-chloro-phenoxy)-2-morpholin-4-yl-pyrimidin-5-ylI -N-methyl-isobutyramide as a colorless foam, MS (ISP): 603.0 Example 67 2- (3,5-Bis-trifluoromethyl-phenyl)-N- [4-(2-chloro-phenoxy)-2- (4-methyl-piperazin-l- In an analogous manner to that described in Example 49 there was obtained from 2-(3,5bis-trifluoromethyl-phenyl)-N- 14- (2-chloro-phenoxy)-2-methanesulfonyl-pyrimidin-5yl] -N-methyl-isobutyramide and 1-methylpiperazine 2-(3,5-bis-trifluoromethyl-phenyl)- N- [4-(2-chloro-phenoxy) (4-methyl-piperazin- 1-yl)-pyriinidin-5-yl] -N-methylisobuty-ramide as a colorless foam, MS (ISP): 616.1 Example 68 2- (3,5-Bis-trifluoromethyl-phenyl)-N- [4-(2-chloro-phenoxy)-2-piperazin- 1-yl-pyrimidin- -N-methyl-isobutyramide In an analogous manner to that described in Example 50 there was obtained from 2-(3,5bis-trifluoromethyl-phenyl)-N- [4-(2-chloro-phenoxy)-2-methanesulfonyl-pyrimidin-5yl] -N-methyl-isobutyramide and piperazine 2- (3,5-bis-trifluoromethyl-phenyl) (2chloro-phenoxy)-2-piperazin- 1-yl-pyrimidin-5-yl] -N-methyl-isobutyramide as a colorless foam, MS (TSP): 602.1 (M+H) t Example 69 2-(3,5-Bis-trifluoromethyl-phenyl)-N- [4-(2-chloro-phenoxy)-2- (2-morpholin-4-ylethoxy)-pyrimidin-5-yl] -N-methyl-isobutyramnide In an analogous manner to that described in Example 52 there was obtained from 2-(3,5bis-trifluoromethyl-phenyl)-N- [4-(2-chloro-phenoxy)-2-methanesulfonyl-pyrimidin-5yll -N-methyl-isobutyramide and N-(2-hydroxyethyl)morpholine 2-(3,5-bistrifluoromethyl-phenyl) [4-(2-chloro-phenoxy)-2-(2-morpholin-4-yl-ethoxy) pyrimidin-5-yl]-N-methyl-isobutyramide as a colorless foam, MS (ISP): 647.1 WO 02/42280 PCT/EPOI/13084 42 Example 2- (3,5-Bis-trifluoromethyl-phenyl)-N- [2-(2-dimethylamino-ethoxy)-4- (2-chioro- In an analogous manner to that described in Example 53 there was obtained from 2-(3,5bis-trifiuoromethyl-phenyl)-N- [4-(2-chloro-phenoxy) yl] -N-methyl-isobutyramide and 2-dimethylaminoethanol 2- phenyrl) -N-[12-(2-dimethylamino-ethoxy)-4-(2-chloro-phenoxy)-pyrimidin-5-yl] -Nmethyl-isobutyramide as a colorless foam, MS (ISP): 605.0 H) t Example 71 2-(3,5-Bis-trifluoromethyl-phenyl)-N- [2-(3-dimethylamino-propoxy)-4- (2-chioro- In an analogous manner to that described in Example 54 there was obtained from 2-(3,5bis-trifiuoromethyl-phenyl)-N- [4-(2-chloro-phenoxy) yl] -N-methyl-isobutyramide and 2-dimethylaminopropanol 2-(3,5-bis-trifiuoromethylphen-yl) (2-dimethylamino-ethoxy) -4-(2-chloro-phenoxy)-pyrimidin-5-yl -Nmethyl-isobutyramide as a colorless foam, MS (ISP): 619.1 Example 72 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(2-methyl-4-o-tolyloxy-pyrimidin-5-yl)isobutyramide a) (2-Methyl-4-o-tolyloxy-pyr~imidin-5-yl)-carbamic acid tert.-butyl ester To a solution of 2.50 g (10.24 mmol) 2-methyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid, 1.43 ml triethylamine (10.24 mmol) and 1.9 ml (20.4 mmol) t-butanol in 50 ml THF, 2.2 ml (10.24 mmol) diphenyiphosporylazide were added and the resulting solution heated at refiux for 12 hrs. After evaporation of the solvent, the residue was distributed between

CH

2 Cl 2 and H 2 0. The aquoeus phase was extracted twice with 80 ml CH 2 Cl 2 The combined organic layers were dried (NaSO 4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2

CI

2 MeOH 40:1) to give 1.83 g (56 (2-methylacid tert.-butyl ester as a colorless solid, MS (ISP): 316.3 (M±H) t b) Methyl- (2-methyl-4-o-tolyloxy-pyrimidin-5-yl) -carbamic acid tert.-buty ester To a solution of 1.83 g (5.80 mmol) (2-mnethyl-4-o-tolyloxy-pyrimidin-5-yl)-carbamic acid tert.-butyl ester in 25 ml N,N-dimethylformamnide 0.35 g (68.7 mmol) sodiurnhydride dispersion in mineraloil) was added and the reaction mixture stirred for 1 h. After the addition of 0.65 ml (10.4 mmol) methyl iodide at the reaction mixture was stirred WO 02/42280 PCT/EPOI/13084 43 for 2 hrs. The reaction mixture was poured into 100 ml ice-water and three times extracted with 80 ml CH 2 Cl 2 The combined organic layers were dried (Na 2

SO

4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2 C1 2 /ethyl acetate 40: 1) to give 1.90 g (99 methyl-(2-methyl-4-o-tolyloxy-pyrimidin-5-yl)-carbamic acid tert.butyl ester as a colorless oil, MS (ISP): 330.4 c) Methyl- (2-methyl-4-o-tolyloxvy-pyrimidin-5-yl)-amine To a solution of 1.90 g (5.77 mmol) methyl-(2-methyl-4-o-tolyloxy-pyrimidin-5-yl)carbamic acid tert.-butyl ester in 25 ml CH 2

C

2 2 ml trifluoracetic acid was added and the reaction mixture stirred for 2 hrs. at 40'. The reaction mixture was poured into ice-water and the pH of the solution adjusted to 10 with 1N NaOH solution. The aqueous phase was extracted three times with 80 ml CH 2 Cl 2 The combined organic layers were dried (Na 2

SO

4 filtered and evaporated to give 0.95 g (72 methvl-(2-methyl-4-o-tolyloxy- -amine as a light yellow solid, MS 229.2 d)i 2- (3,5-Bis-trifluoromethyl-phenyL) -N-methv-N-(2-methvl-4-o-tolylox yl) -isobuiyramide To a solution of 0.4 g (1.74 mol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2and 0.6 ml (3.49 mmol) Nethyldiisopropylamine in 15 ml CH 2 Cl 2 a solution of 0.78 g (2.44 mmol) 2-(3,5-bistrifluormethyl-phenyl)-2-methyl-propionyl chloride in 5 ml CH 2

CI

2 was added and the reaction mixture stirred for 12 brs at RT. The reaction mixture was poured into 50 ml N NaOH--solution.The phases were separated and the aqueous phase three times extracted with 80 ml CH 2 Gl 2 The combined organic layers were dried (Na 2

SO

4 filtered and evaporated. The residue was purified by chromatography (SiO 2

CH

2 Cl 2 /MeOH 40: 1) to give 0.82 g (94 2-(3,5-bis-trifiuoromethyl-phenyl)-N-methyl-N-(2-methyl-4-otolyloxy--pyrimidin-5-yl)-isobutyramide as a white foam, MS (ISP): 511.1 Example 73 2- (3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(2-phenyl-4-o-tolyloxy-pyriniidin-5-yl)isobutyramide In an analougous manner to that described in Examle 72 a) there was obtained from 2acid, diphenylphosphorylazide and t-butanol (2-phenyl-4-o-tolyloxy-pyrimidin-5-yl)-carbamic acid tert.-butyl ester, which was methylated with methyliodide and than deprotected with trifluoracetic acid according to Example 72 b) The resulting methyl-( 2-phenyl-4-o-tolyloxy-pyrimidin-5-yl)-amine was treated with 2- (3,5-bis-trifiuormethyl-phenyl)-2-methyl-propionyl chloride as described in Example 72 e) to give 2- (3,5-bis-trifluoromethyl-phenyl)-N-mnethyl-N-(2-phenyl-4-oas a white foam, MS (ISP): 574.1 (M±H) t WO 02/42280 PCT/EP01/13084 -44- Example A Tablets of the following composition are manufactured in the usual manner: mg/tablet Active substance Lactose Corn starch Microcrystalline cellulose 34 Magnesium stearate 1 Tablet weight 100 Example B Capsules of the following composition are manufactured: mg/capsule Active substance Lactose 155 Corn starch Talc Capsule fill weight 200 The active substance, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer, the talc is added thereto and mixed thoroughly. The mixture is filled by machine into hard gelatine capsules.

Example C Suppositories of the following composition are manufactured: mg/supp.

Active substance Suppository mass 1285 Total 1300 The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45 0 C. Thereupon, the finely powdered active substance is added thereto and WO 02/42280 PCT/EP01/13084 stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool, the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.

Claims (16)

1. A compound of the formula: R2 y (R 4 )m R N R 3 R 3 wherein R' is lower alkyl, lower alkoxy, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, S(0) 2 -lower alkyl, -N(Ra)-(CH 2 )n-N(Rb) 2 -O-(CH 2 )n-N(RC) 2 -N(Rd) 2 or a cyclic tertiary amine of the group having no or one additional heteroatom, selected from N, O or S, said cyclic tertiary amine being connected directly to a pyrimidine ring of formula 1 or connected to said pyrimidine ring of formula 1 via the linker -O(CH 2 R 2 is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; R3/R3 are, independently from each other, hydrogen or lower alkyl; (R 4 )m are, independently from each other in the case where m is not 0 or 1, halogen, trifluoromethyl or lower alkoxy; R' is hydrogen or lower alkyl; R, R a R b R c Rd, Re, R f are, independently from each other, hydrogen or lower alkyl; X is N(Rf)C(O)-; Y is -SO 2 or n is 1,2,3 or 4; and m is 0, 1 or 2; or a pharmaceutically acceptable acid addition salt thereof.

2. A compound of formula I according to claim 1, wherein R' is a cyclic tertiary amine of the group [R:\LIBA]06752.doc:JJP 47

3. A compound of formula I according to claim 2, wherein R' is -O-(CH 2 )n- cyclic tertiary amine of the group

4. A compound of formula I according to claim 1, wherein R' is the group -0- (CH 2 )-NRc 2 A compound of formula I according to claim 1, wherein X is -N(CH 3 and Yis

6. A compound of formula I according to claim 5, wherein R 1 is -S-lower alkyl.

7. A compound of formula I according to claim 5, which is 2-35bstilooehlpey)Nmty--2mtyslay---oyoy 2-(3,5bstilooehlpey)N[-4fuoopeoy--ehlufnlprmdn or 2-35bstilooehlpey)N[-2choopeoy--ehlufnlprmdn

8. A compound of formula Iaccording to claim 5, wherein R 1 is a cyclic tertiary amine of the group

9. A compound of formula I according to claim 8, which is 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-methyl-N-II2-(4-methyl-piperazin- 1-yl)-4-o- 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-piperazin- 1-yl-4-o-tolyloxy-pyrimidin- 2-(3,5bstilooehlpenl--4(-loopeox)2(-ehlpprz 1 -yl)- -yl]-N-methyl-isobutyramide, R:LIBA]067 52.doc:JJ P 48 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenoxy)-2-piperazin- 1-yl-pyrimidin- 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenoxy)-2-morpholin-4-yl-pyrmidin- -N-methyl-isobutyramide, 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenoxy)-2-(4-methyl-piperazin- l-yl)- or 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenoxy)-2-piperazin- 1-yl-pyrimidin- A compound of formula I according to claim 5, wherein R' is i0 -N(R a)(CH 2 2*

11. A compound of formula I according to claim 10, which is 2-(3 ,5 -bis-trifluoromethyl-phenyl)-N-[2-(2-dimethylamino-ethylamino)-4-o-tolyloxy- -yl]-N-methyl-isobutyramide or 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-112-(2-dimethylamino-ethylamino)-4-(4-fluoro- phenoxy)-pyrimidin-5 -yl]-N-methyl-isobutyramide.

12. A compound of formula I according to claim 5, wherein R' is a C2, cyclic tertiary amine of the group

13. A compound of formula I according to claim 12, which is 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-methyl-N-12-(2-morpholin-4-yl-ethoxy)-4-o- 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenoxy)-2-(2-morpholin-4-yl-

14. A compound of formula I according to claim 5, wherein R' is -O-(CH 2 ),NRc 2 A compound of formula I according to claim 14, which is 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-[2-(2-dimethylamino-ethoxy)-4-o-tolyloxy- 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-[2-(3-dimethylamnino-propoxy)-4-o-tolyloxy- 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-172-(2-dimethylamino-ethoxy)-4-(4-fluoro-phenoxy)- 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-II2-(3-dimethylamino-propoxy)-4-(4-fluoro- [R:\LIBA]06752.doc:JJP 4 -49- 2-(3 ,5-bis-trifluoromethyl-phenyl)-N- [2-(2-dimethylamino-ethoxy)-4-(2-chloro- -yl] -N-methyl-isobutyramide or 2-(3 ,5 -bis-trifluoromethyl-phenyl)-N-[2-(3 -dimethylamino-propoxy)-4-(2-chloro- -ylj]-N-methyl-isobutyramide.

16. A medicament containing an effective amount of a compound of formula I according to claim 1 and a pharmaceutically acceptable excipient.

17. A compound of formula I according to claim 1 wherein X is -N(Rf)C(O)- wherein Rf is lower alkyl, Y is and R 2 is lower alkyl.

18. A compound of formula 1 according to claim 17 wherein the compound is 2-(3 ,5 -bis-trifluoromethyl-phenyl)-N-(2-methanesulfonyl-4-o-tolyloxy-pyrimidinl 5 -yl)- N-methyl-isobutyramide; 2-(3 ,5 -bis-trifluoromethyl-phenyl)-N-methyl-N-(2-methyl-4-o-tolyloxy-pyriflidin- 5 -yl)- isobutyramide; or 2-(3 ,5-bis-trifluoromethy1-phenyl)-N-methy-N-(2-phenyl-4-o-tolyloxy-pyrimidin- -yl)- isobutyramide.

19. A compound of formula I according to claim 1 wherein X is -N(Rf)C(O)- wherein Rf is lower alkyl, Y is and R 2 is halogen. A compound of formnula 1 according to claim 19 wherein the compound is 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-Ii4-(4-,fluoro-phenoxy)-2-methaneSulfonyl- pyrimidin-5 -yl]-N-methyl-isobutyramide; 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenoxy)-2-(4-methyl-piperazil- l-yl)- -yl] -N-methyl-isobutyramide; 2-(3 ,5 -bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenoxy)-2-(2-morpholin- 4 -yl- -N-methyl-isobutyramide; 2-(3 ,5 -bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenoxy)-2-methanesulfonyl- -N-methyl-isobutyramide; 2-(3,5bstilooehlpey)N[ 2cloopeoy--opoi--lprmdn or 2-(3 ,5-bis-trifluoromethyl-phenyl)-N- [4-(2-chloro-phenoxy)-2-piperazin- 1-yl-pyrimidin- Dated 22 November, 2004 F. Hoffmann-La Roche AG Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [R:\LIBA]06752.doc:JJP